Corneal transplantation is the oldest, most common, and arguably, the most successful form of solid tissue grafting. In the U.S. alone, over 40,000 corneal transplants are performed each year. Even though HLA typing is not performed and topical corticosteroids are the only immunosuppressive agents used, 90% of the corneal transplants will survive the first year. No other form of solid organ transplantation can boast thi success rate under the same conditions. However, in spite of this immune privilege, corneal allografts can fail, with immune rejection being the leading cause of corneal allograft failure. Thus, the long-range goal of this project is to better understand the underlying mechanisms that contribute to immune privilege of corneal allografts and to characterize and hopefully, reverse those conditions that rob the corneal allograft of its immune privilege and lead to allograft rejection. A mouse model of penetrating keratoplasty will be used in prospective studies that address three specific aims pursuant to these long range goals. The first specific aim explores the immune mechanisms whereby allergic diseases such as asthma and allergic conjunctivitis abolish corneal immune privilege and profoundly increase the incidence and tempo of corneal allograft rejection. The second specific aim explores the dramatically different roles of theTh1 cytokine, interferon-y (IFN-y) in different categories of mismatched corneal allografts. In the case of MHC + multiple minor histocompatibility (H)-mismatched grafts, IFN-y is required for graft survival. By contrast, in MHC-matched, minor H mismatched grafts IFN-y promotes corneal allograft rejection. The third specific aim characterizes a recently discovered finding, which demonstrates that corneal surgery jeopardizes the survival of subsequent corneal allografts, even corneal allografts from donors completely unrelated to the donor of the corneal allograft and even more impressively, in corneal allografts placed in the contralateral eye! We have termed this phenomenon Sympathetic Abrogation of Immune Privilege (SAIP). SAIP may contribute to the sharp increase in corneal allograft rejection that occurs in patients who receive subsequent corneal allografts from donors unrelated to the donors of the first corneal allograft.